FIGURE 1.

Human social signal transduction. Social signal transduction is the process by which the CNS monitors and appraises the (1) social environment, interprets social signals and behaviors, and judges the extent to which the surrounding environment is socially safe versus threatening. These appraisals are subserved by the (2) social brain. When a threat is subjectively perceived, the brain activates a multilevel response that is mediated by several potential social signal transduction pathways—namely, the (3) SNS, (4) HPA axis,(5) vagus nerve, and (6) meningeal lymphatic vessels. These pathways enable the brain to alter genome-wide transcriptional dynamics in peripheral tissues (e.g., white blood cells). In response to social adversity, the main end products of the SNS, epinephrine and norepinephrine, suppress transcription of antiviral type interferon genes (e.g., IFNA and IFNB) and upregulate transcription of pro-inflammatory immune response genes (e.g., IL1B, IL6, and TNF), known as the Conserved Transcriptional Response to Adversity. In contrast, the main end product of the HPA axis, cortisol, generally reduces both antiviral and inflammatory gene expression (although chronic social stress can trigger glucocorticoid insensitivity/resistance, which can allow increased inflammatory gene expression). The vagus nerve, in turn, plays a putative role in suppressing inflammatory activity, whereas meningeal lymphatic vessels enable immune mediators originating in the CNS to traffic to the periphery, where they can potentially exert systemic effects. CNS, central nervous system; HPA, hypothalamic–pituitary–adrenal; IFNA, interferon alpha; IFNB, interferon beta; IL1B, interleukin 1 beta; IL6, interleukin 6; SNS, sympathetic nervous system; TNF, tumor necrosis factor. Republished from Ref. 92 with permission from Annual Reviews.